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I2366 Preserve enhanced stereo in reactions (#2377)

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* Potential implementation of copying enhanced stereo groups

Copies the enhanced stereo if all atoms in the reactant
end up in the same molecule of the product with valid
ChiralTags.

Current implementation: Only copy StereoGroup if all atoms are "valid" in the product.
Possible implementation: Copy StereoGroup for all atoms that are "valid" in the product.

Details:
Uses ChiralTag invalidation to decide whether StereoGroup should be copied. If
the product atoms have valid ChiralTag, then the reaction was able to
meaningfully propogate chirality from the reactant to the product. This means
that it is also meaningful to propogate the StereoGroup from the reactant to
the product.

The only exception to this is if the product template defines a specific
absolute configuration for an atom. This means that the reaction defines the
stereochemistry for the atom, so the stereochemistry of that atom is no longer
relative.

If an atom from a reactant StereoGroup appears multiple times in the product,
all copies of that atom are put in the same product StereoGroup.

Still developing test cases.

    from rdkit import Chem
    from rdkit.Chem import AllChem

    # Duplicate a molecule example:
    mol1 = Chem.MolFromSmiles('Cl[C@@H](Br)C[C@H](Br)CCO |&1:1,4|')
    mol2 = Chem.MolFromSmiles('CC(=O)C')
    rxn = AllChem.ReactionFromSmarts('[O:1].[C:2]=O>>[O:1][C:2][O:1]')
    for prods in rxn.RunReactants([mol1, mol2]):
        for p in prods:
            for a in p.GetAtoms():
                for k in a.GetPropsAsDict():
                    a.ClearProp(k)
            print(Chem.MolToCXSmiles(p))

Output:

[21:26:08] product atom-mapping number 1 found multiple times.
CC(C)(OCC[C@@H](Br)C[C@@H](Cl)Br)OCC[C@@H](Br)C[C@@H](Cl)Br |&1:6,9,15,18

* Issue 2366: Documentation and fix stereo group invalidation

Adds some documentation to EnhancedStereo.md

Also invalidates StereoGroup if a reaction specifies the
stereochemistry of a center. This destroys the relative
relationship of the center to other centers.

* Demo python file examples for Enhanced Stereochemistry in reactions

This is not intended to be pushed. These probably will become test
cases. For the output looks like this:

    0a. Reaction preserves stereo:
      [C@:1]>>[C@:1]
        F[C@H](Cl)Br |o1:1|
          >>
          F[C@H](Cl)Br |o1:1|

    0b. Reaction preserves stereo:
      [C@:1]>>[C@:1]
        F[C@@H](Cl)Br |&1:1|
          >>
          F[C@@H](Cl)Br |&1:1|

    0c. Reaction preserves stereo:
      [C@:1]>>[C@:1]
        FC(Cl)Br
          >>
          FC(Cl)Br

    1a. Reaction ignores stereo:
      [C:1]>>[C:1]
        F[C@H](Cl)Br |a:1|
          >>
          F[C@H](Cl)Br |a:1|

    1b. Reaction ignores stereo:
      [C:1]>>[C:1]
        F[C@@H](Cl)Br |&1:1|
          >>
          F[C@@H](Cl)Br |&1:1|

    1c. Reaction ignores stereo:
      [C:1]>>[C:1]
        FC(Cl)Br
          >>
          FC(Cl)Br

    2a. Reaction inverts stereo:
      [C@:1]>>[C@@:1]
        F[C@H](Cl)Br |o1:1|
          >>
          F[C@@H](Cl)Br |o1:1|

    2b. Reaction inverts stereo:
      [C@:1]>>[C@@:1]
        F[C@@H](Cl)Br |&1:1|
          >>
          F[C@H](Cl)Br |&1:1|

    2c. Reaction inverts stereo:
      [C@:1]>>[C@@:1]
        FC(Cl)Br
          >>
          FC(Cl)Br

    3a. Reaction destroys stereo:
      [C@:1]>>[C:1]
        F[C@H](Cl)Br |o1:1|
          >>
          FC(Cl)Br

    3b. Reaction destroys stereo:
      [C@:1]>>[C:1]
        F[C@@H](Cl)Br |&1:1|
          >>
          FC(Cl)Br

    3c. Reaction destroys stereo:
      [C@:1]>>[C:1]
        FC(Cl)Br
          >>
          FC(Cl)Br

    3d. Reaction destroys stereo (but preserves unaffected group):
      [C@:1]F>>[C:1]F
        F[C@H](Cl)[C@@H](Cl)Br |o1:1,&2:3|
          >>
          FC(Cl)[C@@H](Cl)Br |&1:3|

    3e. Reaction destroys stereo:
      [C@:1]F>>[C:1]F
        F[C@H](Cl)[C@@H](Cl)Br |&1:1,3|
          >>
          FC(Cl)[C@@H](Cl)Br

    4a. Reaction creates stereo:
      [C:1]>>[C@@:1]
        F[C@H](Cl)Br |o1:1|
          >>
          F[C@@H](Cl)Br

    4b. Reaction creates stereo:
      [C:1]>>[C@@:1]
        F[C@@H](Cl)Br |&1:1|
          >>
          F[C@@H](Cl)Br

    4c. Reaction creates stereo:
      [C:1]>>[C@@:1]
        FC(Cl)Br
          >>
          F[C@@H](Cl)Br

    4d. Reaction creates stereo (preserve unaffected group):
      [C:1]F>>[C@@:1]F
        F[C@H](Cl)[C@@H](Cl)Br |o1:1,&2:3|
          >>
          F[C@@H](Cl)[C@@H](Cl)Br |&1:3|

    4e. Reaction creates stereo:
      [C:1]F>>[C@@:1]F
        F[C@H](Cl)[C@@H](Cl)Br |o1:1,3|
          >>
          F[C@@H](Cl)[C@@H](Cl)Br

    5a. Reaction preserves unrelated stereo:
      [C@:1]F>>[C@:1]F
        F[C@H](Cl)[C@@H](Cl)Br |o1:3|
          >>
          F[C@H](Cl)[C@@H](Cl)Br |o1:3|

    5b. Reaction ignores unrelated stereo:
      [C:1]F>>[C:1]F
        F[C@H](Cl)[C@@H](Cl)Br |o1:3|
          >>
          F[C@H](Cl)[C@@H](Cl)Br |o1:3|

    5c. Reaction inverts unrelated stereo:
      [C@:1]F>>[C@@:1]F
        F[C@H](Cl)[C@@H](Cl)Br |o1:3|
          >>
          F[C@@H](Cl)[C@@H](Cl)Br |o1:3|

    5d. Reaction destroys unrelated stereo:
      [C@:1]F>>[C:1]F
        F[C@H](Cl)[C@@H](Cl)Br |o1:3|
          >>
          FC(Cl)[C@@H](Cl)Br |o1:3|

    5e. Reaction creates unrelated stereo:
      [C:1]F>>[C@@:1]F
        F[C@H](Cl)[C@@H](Cl)Br |o1:3|
          >>
          F[C@@H](Cl)[C@@H](Cl)Br |o1:3|

    6e. Reaction splits StereoGroup atoms into two Mols:
      [C:1]OO[C:2]>>[C:2]O.O[C:1]
        F[C@H](Cl)OO[C@@H](Cl)Br |o1:1,5|
          >>
          O[C@@H](Cl)Br + O[C@H](F)Cl
          >>
          O[C@H](F)Cl + O[C@@H](Cl)Br

    7. Add two copies:
      [O:1].[C:2]=O>>[O:1][C:2][O:1]
        Cl[C@@H](Br)C[C@H](Br)CCO |&1:1,4| + CC(=O)C
    [17:15:38] product atom-mapping number 1 found multiple times.
          >>
          CC(C)(OCC[C@@H](Br)C[C@@H](Cl)Br)OCC[C@@H](Br)C[C@@H](Cl)Br |&1:6,9,15,18|

    8. Add two copies:
      [O:1].[C:2]=O>>[O:1][C:2][O:1]
        Cl[C@@H](Br)C[C@H](Br)CCO |&1:1,4| + CC(=O)C
    [17:15:38] product atom-mapping number 1 found multiple times.
          >>
          CC(C)(OCC[C@@H](Br)C[C@@H](Cl)Br)OCC[C@@H](Br)C[C@@H](Cl)Br |&1:6,9,15,18|

* Updates StereoGroup strategy in reactions to copy all possible atoms.

Copy all atoms for which the stereochemistry was not created or destroyed
in the reaction. Any StereoGroup which has at least one atom will appear
in the product.

Also updates the documentation to match this description, and adds C++
and Python tests which fail before this PR and pass after. The Python
tests are more extensive.

Test output was validated by hand (especially the stereo groups
generated. I'm less confident in the reaction processing in my head,
but I truested the existing validation there.)

For future diagnosis: Python unittest failures will look like:

    AssertionError: 'F[C@H](Cl)Br' != 'F[C@H](Cl)Br |&1:1|'
    - F[C@H](Cl)Br
    + F[C@H](Cl)Br |&1:1|
    ?             +++++++

For future diagnosis: C++ Catch2 failures will look like:

      CHECK( MolToCXSmiles(*p) == "F[C@H](Cl)Br |o1:1|" )
    with expansion:
      "FC(Cl)[C@@H](Cl)Br |&1:3|"
      ==
      "F[C@H](Cl)Br |o1:1|"

* Add a couple of new tests.

* rename "relative" to "enhanced"
some reformatting

* Factor out test helper function.

* Actually, enhanced stereo groups are exposed ot Python

* Added discussion of enhanced stereochemistry in reactions to docs

* Fix new test
This commit is contained in:
Dan N
2019-04-06 21:06:28 -07:00
committed by Greg Landrum
parent 941d7abb5f
commit 2bcb7ea692
6 changed files with 464 additions and 47 deletions
Download Patch File Download Diff File Expand all files Collapse all files

107
Code/GraphMol/ChemReactions/ReactionRunner.cpp
View File

@@ -129,13 +129,12 @@ bool getReactantMatches(const MOL_SPTR_VECT &reactants,
bool recurseOverReactantCombinations(
const VectVectMatchVectType &matchesByReactant,
VectVectMatchVectType &matchesPerProduct, unsigned int level,
VectMatchVectType combination,
unsigned int maxProducts) {
VectMatchVectType combination, unsigned int maxProducts) {
unsigned int nReactants = matchesByReactant.size();
URANGE_CHECK(level, nReactants);
PRECONDITION(combination.size() == nReactants, "bad combination size");
if(maxProducts && matchesPerProduct.size() >= maxProducts) {
if (maxProducts && matchesPerProduct.size() >= maxProducts) {
return false;
}
@@ -146,15 +145,15 @@ bool recurseOverReactantCombinations(
prod[level] = *reactIt;
if (level == nReactants - 1) {
// this is the bottom of the recursion:
if(maxProducts && matchesPerProduct.size() >= maxProducts) {
if (maxProducts && matchesPerProduct.size() >= maxProducts) {
keepGoing = false;
break;
}
matchesPerProduct.push_back(prod);
} else {
keepGoing = recurseOverReactantCombinations(matchesByReactant, matchesPerProduct,
level + 1, prod, maxProducts);
keepGoing = recurseOverReactantCombinations(
matchesByReactant, matchesPerProduct, level + 1, prod, maxProducts);
}
}
return keepGoing;
@@ -184,16 +183,15 @@ void updateImplicitAtomProperties(Atom *prodAtom, const Atom *reactAtom) {
void generateReactantCombinations(
const VectVectMatchVectType &matchesByReactant,
VectVectMatchVectType &matchesPerProduct,
unsigned int maxProducts) {
VectVectMatchVectType &matchesPerProduct, unsigned int maxProducts) {
matchesPerProduct.clear();
VectMatchVectType tmp;
tmp.clear();
tmp.resize(matchesByReactant.size());
if (!recurseOverReactantCombinations(matchesByReactant, matchesPerProduct, 0, tmp, maxProducts)) {
BOOST_LOG(rdWarningLog)
<< "Maximum product count hit " << maxProducts << ", stopping reaction early...\n";
if (!recurseOverReactantCombinations(matchesByReactant, matchesPerProduct, 0,
tmp, maxProducts)) {
BOOST_LOG(rdWarningLog) << "Maximum product count hit " << maxProducts
<< ", stopping reaction early...\n";
}
} // end of generateReactantCombinations()
@@ -397,13 +395,13 @@ void checkProductChirality(Atom::ChiralType reactantChirality,
switch (flagVal) {
case 0:
// reaction doesn't have anything to say about the chirality
// FIX: should we clear the chirality or leave it alone? for now we leave
// it alone
// productAtom->setChiralTag(Atom::ChiralType::CHI_UNSPECIFIED);
productAtom->setChiralTag(reactantChirality);
break;
case 1:
// inversion
// reaction inverts chirality
if (reactantChirality != Atom::CHI_TETRAHEDRAL_CW &&
reactantChirality != Atom::CHI_TETRAHEDRAL_CCW) {
BOOST_LOG(rdWarningLog)
@@ -414,14 +412,17 @@ void checkProductChirality(Atom::ChiralType reactantChirality,
}
break;
case 2:
// reaction retains chirality:
// retention: just set to the reactant
productAtom->setChiralTag(reactantChirality);
break;
case 3:
// reaction destroys chirality:
// remove stereo
productAtom->setChiralTag(Atom::CHI_UNSPECIFIED);
break;
case 4:
// reaction creates chirality.
// set stereo, so leave it the way it was in the product template
break;
default:
@@ -466,8 +467,7 @@ void setReactantAtomPropertiesToProduct(Atom *productAtom,
// One might be tempted to copy over the reactant atom's chirality into the
// product atom if chirality is not specified on the product. This would be a
// very bad idea because the order of bonds will almost certainly change on
// the
// atom and the chirality is referenced to bond order.
// the atom and the chirality is referenced to bond order.
// --------- --------- --------- --------- --------- ---------
// While we're here, set the stereochemistry
@@ -669,8 +669,7 @@ void checkAndCorrectChiralityOfMatchingAtomsInProduct(
continue;
}
// we can only do something sensible here if we have the same number of
// bonds
// in the reactants and the products:
// bonds in the reactants and the products:
if (reactantAtom.getDegree() != productAtom->getDegree()) {
continue;
}
@@ -732,13 +731,14 @@ void checkAndCorrectChiralityOfMatchingAtomsInProduct(
}
}
// Check the chirality of atoms not directly involved in the reaction
void checkAndCorrectChiralityOfProduct(
const std::vector<const Atom *> &chiralAtomsToCheck, RWMOL_SPTR product,
ReactantProductAtomMapping *mapping) {
for (auto reactantAtom : chiralAtomsToCheck) {
CHECK_INVARIANT(reactantAtom->getChiralTag() != Atom::CHI_UNSPECIFIED,
"missing atom chirality.");
unsigned int reactAtomDegree =
const auto reactAtomDegree =
reactantAtom->getOwningMol().getAtomDegree(reactantAtom);
for (unsigned i = 0;
i < mapping->reactProdAtomMap[reactantAtom->getIdx()].size(); i++) {
@@ -753,12 +753,9 @@ void checkAndCorrectChiralityOfProduct(
// If the number of bonds to the atom has changed in the course of the
// reaction we're lost, so remove chirality.
// A word of explanation here: the atoms in the chiralAtomsToCheck set
// are
// not explicitly mapped atoms of the reaction, so we really have no
// idea what
// to do with this case. At the moment I'm not even really sure how
// this
// could happen, but better safe than sorry.
// are not explicitly mapped atoms of the reaction, so we really have
// no idea what to do with this case. At the moment I'm not even really
// sure how this could happen, but better safe than sorry.
productAtom->setChiralTag(Atom::CHI_UNSPECIFIED);
} else if (reactantAtom->getChiralTag() == Atom::CHI_TETRAHEDRAL_CW ||
reactantAtom->getChiralTag() == Atom::CHI_TETRAHEDRAL_CCW) {
@@ -794,6 +791,51 @@ void checkAndCorrectChiralityOfProduct(
} // end of loop over chiralAtomsToCheck
}
///
// Copy enhanced stereo groups from one reactant to the product
// stereo groups are copied if any atoms are in the product with
// the stereochemical information from the reactant preserved.
void copyEnhancedStereoGroups(const ROMol &reactant, RWMOL_SPTR product,
const ReactantProductAtomMapping &mapping) {
std::vector<StereoGroup> new_stereo_groups;
for (const auto &sg : reactant.getStereoGroups()) {
std::vector<Atom *> atoms;
for (auto &&reactantAtom : sg.getAtoms()) {
auto productAtoms = mapping.reactProdAtomMap.find(reactantAtom->getIdx());
if (productAtoms == mapping.reactProdAtomMap.end()) {
continue;
}
for (auto &&productAtomIdx : productAtoms->second) {
auto productAtom = product->getAtomWithIdx(productAtomIdx);
// If chirality destroyed by the reaction, skip the atom
if (productAtom->getChiralTag() == Atom::CHI_UNSPECIFIED) {
continue;
}
// If chirality defined explicitly by the reaction, skip the atom
int flagVal = 0;
productAtom->getPropIfPresent(common_properties::molInversionFlag,
flagVal);
if (flagVal == 4) {
continue;
}
atoms.push_back(productAtom);
}
}
if (!atoms.empty()) {
new_stereo_groups.emplace_back(sg.getGroupType(), std::move(atoms));
}
}
if (!new_stereo_groups.empty()) {
auto &existing_sg = product->getStereoGroups();
new_stereo_groups.insert(new_stereo_groups.end(), existing_sg.begin(),
existing_sg.end());
product->setStereoGroups(std::move(new_stereo_groups));
}
}
void generateProductConformers(Conformer *productConf, const ROMol &reactant,
ReactantProductAtomMapping *mapping) {
if (!reactant.getNumConformers()) {
@@ -880,10 +922,14 @@ void addReactantAtomsAndBonds(const ChemicalReaction &rxn, RWMOL_SPTR product,
// ---------- ---------- ---------- ---------- ---------- ----------
// now we need to loop over atoms from the reactants that were chiral but not
// directly involved in the reaction in order to make sure their chirality
// hasn't
// been disturbed
// hasn't been disturbed
checkAndCorrectChiralityOfProduct(chiralAtomsToCheck, product, mapping);
// ---------- ---------- ---------- ---------- ---------- ----------
// Copy enhanced StereoGroup data from reactant to product if it is
// still valid. Uses ChiralTag checks above.
copyEnhancedStereoGroups(*reactant, product, *mapping);
// ---------- ---------- ---------- ---------- ---------- ----------
// finally we may need to set the coordinates in the product conformer:
if (productConf) {
@@ -902,7 +948,7 @@ MOL_SPTR_VECT generateOneProductSet(
// if any of the reactants have a conformer, we'll go ahead and
// generate conformers for the products:
bool doConfs = false;
BOOST_FOREACH (ROMOL_SPTR reactant, reactants) {
for (auto &reactant : reactants) {
if (reactant->getNumConformers()) {
doConfs = true;
break;
@@ -975,9 +1021,8 @@ std::vector<MOL_SPTR_VECT> run_Reactants(const ChemicalReaction &rxn,
// we now have matches for each reactant, so we can start creating products:
// start by doing the combinatorics on the matches:
VectVectMatchVectType reactantMatchesPerProduct;
ReactionRunnerUtils::generateReactantCombinations(matchesByReactant,
reactantMatchesPerProduct,
maxProducts);
ReactionRunnerUtils::generateReactantCombinations(
matchesByReactant, reactantMatchesPerProduct, maxProducts);
productMols.resize(reactantMatchesPerProduct.size());
for (unsigned int productId = 0; productId != productMols.size();

178
Code/GraphMol/ChemReactions/Wrap/testReactionWrapper.py
View File

@@ -717,5 +717,183 @@ M END
self.assertEqual(len(prods), 1)
def _getProductCXSMILES(product):
"""
Clear properties.
Mapping properties show up in CXSMILES make validation less readable.
"""
for a in product.GetAtoms():
for k in a.GetPropsAsDict():
a.ClearProp(k)
return Chem.MolToCXSmiles(product)
def _reactAndSummarize(rxn_smarts, *smiles):
"""
Run a reaction and combine the products in a single string.
Makes errors readable ish
"""
rxn = rdChemReactions.ReactionFromSmarts(rxn_smarts)
mols = [Chem.MolFromSmiles(s) for s in smiles]
products = []
for prods in rxn.RunReactants(mols):
products.append(' + '.join(map(_getProductCXSMILES, prods)))
products = ' OR '.join(products)
return products
class StereoGroupTests(unittest.TestCase):
def test_reaction_preserves_stereo(self):
"""
StereoGroup atoms are in the reaction, but the reaction doesn't affect
the chirality at the stereo centers
-> preserve stereo group
"""
reaction = '[C@:1]>>[C@:1]'
reactants = ['F[C@H](Cl)Br |o1:1|', 'F[C@@H](Cl)Br |&1:1|', 'FC(Cl)Br']
for reactant in reactants:
products = _reactAndSummarize(reaction, reactant)
self.assertEqual(products, reactant)
def test_reaction_ignores_stereo(self):
"""
StereoGroup atoms are in the reaction, but the reaction doesn't specify the
chirality at the stereo centers
-> preserve stereo group
"""
reaction = '[C:1]>>[C:1]'
reactants = ['F[C@H](Cl)Br |o1:1|', 'F[C@@H](Cl)Br |&1:1|', 'FC(Cl)Br']
for reactant in reactants:
products = _reactAndSummarize(reaction, reactant)
self.assertEqual(products, reactant)
def test_reaction_inverts_stereo(self):
"""
StereoGroup atoms are in the reaction, and the reaction inverts the specified
chirality at the stereo centers.
-> preserve stereo group
"""
reaction = '[C@:1]>>[C@@:1]'
products = _reactAndSummarize(reaction, 'F[C@H](Cl)Br |o1:1|')
self.assertEqual(products, 'F[C@@H](Cl)Br |o1:1|')
products = _reactAndSummarize(reaction, 'F[C@@H](Cl)Br |&1:1|')
self.assertEqual(products, 'F[C@H](Cl)Br |&1:1|')
products = _reactAndSummarize(reaction, 'FC(Cl)Br')
self.assertEqual(products, 'FC(Cl)Br')
def test_reaction_destroys_stereo(self):
"""
StereoGroup atoms are in the reaction, and the reaction destroys the specified
chirality at the stereo centers
-> invalidate stereo center, preserve the rest of the stereo group.
"""
reaction = '[C@:1]>>[C:1]'
products = _reactAndSummarize(reaction, 'F[C@H](Cl)Br |o1:1|')
self.assertEqual(products, 'FC(Cl)Br')
products = _reactAndSummarize(reaction, 'F[C@@H](Cl)Br |&1:1|')
self.assertEqual(products, 'FC(Cl)Br')
products = _reactAndSummarize(reaction, 'FC(Cl)Br')
self.assertEqual(products, 'FC(Cl)Br')
reaction = '[C@:1]F>>[C:1]F'
# Reaction destroys stereo (but preserves unaffected group
products = _reactAndSummarize(reaction,
'F[C@H](Cl)[C@@H](Cl)Br |o1:1,&2:3|')
self.assertEqual(products, 'FC(Cl)[C@@H](Cl)Br |&1:3|')
# Reaction destroys stereo (but preserves the rest of the group
products = _reactAndSummarize(reaction, 'F[C@H](Cl)[C@@H](Cl)Br |&1:1,3|')
self.assertEqual(products, 'FC(Cl)[C@@H](Cl)Br |&1:3|')
def test_reaction_defines_stereo(self):
"""
StereoGroup atoms are in the reaction, and the reaction creates the specified
chirality at the stereo centers
-> remove the stereo center from
-> invalidate stereo group
"""
products = _reactAndSummarize('[C:1]>>[C@@:1]', 'F[C@H](Cl)Br |o1:1|')
self.assertEqual(products, 'F[C@@H](Cl)Br')
products = _reactAndSummarize('[C:1]>>[C@@:1]', 'F[C@@H](Cl)Br |&1:1|')
self.assertEqual(products, 'F[C@@H](Cl)Br')
products = _reactAndSummarize('[C:1]>>[C@@:1]', 'FC(Cl)Br')
self.assertEqual(products, 'F[C@@H](Cl)Br')
# Remove group with defined stereo
products = _reactAndSummarize('[C:1]F>>[C@@:1]F',
'F[C@H](Cl)[C@@H](Cl)Br |o1:1,&2:3|')
self.assertEqual(products, 'F[C@@H](Cl)[C@@H](Cl)Br |&1:3|')
# Remove atoms with defined stereo from group
products = _reactAndSummarize('[C:1]F>>[C@@:1]F',
'F[C@H](Cl)[C@@H](Cl)Br |o1:1,3|')
self.assertEqual(products, 'F[C@@H](Cl)[C@@H](Cl)Br |o1:3|')
def test_stereogroup_is_spectator_to_reaction(self):
"""
StereoGroup atoms are not in the reaction
-> stereo group is unaffected
"""
# 5a. Reaction preserves unrelated stereo
products = _reactAndSummarize('[C@:1]F>>[C@:1]F',
'F[C@H](Cl)[C@@H](Cl)Br |o1:3|')
self.assertEqual(products, 'F[C@H](Cl)[C@@H](Cl)Br |o1:3|')
# 5b. Reaction ignores unrelated stereo'
products = _reactAndSummarize('[C:1]F>>[C:1]F',
'F[C@H](Cl)[C@@H](Cl)Br |o1:3|')
self.assertEqual(products, 'F[C@H](Cl)[C@@H](Cl)Br |o1:3|')
# 5c. Reaction inverts unrelated stereo'
products = _reactAndSummarize('[C@:1]F>>[C@@:1]F',
'F[C@H](Cl)[C@@H](Cl)Br |o1:3|')
self.assertEqual(products, 'F[C@@H](Cl)[C@@H](Cl)Br |o1:3|')
# 5d. Reaction destroys unrelated stereo' 1:3|
products = _reactAndSummarize('[C@:1]F>>[C:1]F',
'F[C@H](Cl)[C@@H](Cl)Br |o1:3|')
self.assertEqual(products, 'FC(Cl)[C@@H](Cl)Br |o1:3|')
# 5e. Reaction assigns unrelated stereo'
products = _reactAndSummarize('[C:1]F>>[C@@:1]F',
'F[C@H](Cl)[C@@H](Cl)Br |o1:3|')
self.assertEqual(products, 'F[C@@H](Cl)[C@@H](Cl)Br |o1:3|')
def test_reaction_splits_stereogroup(self):
"""
StereoGroup atoms are split into two products by the reaction
-> Should the group be invalidated or trimmed?
"""
products = _reactAndSummarize('[C:1]OO[C:2]>>[C:2]O.O[C:1]',
'F[C@H](Cl)OO[C@@H](Cl)Br |o1:1,5|')
# Two product sets, each with two mols:
self.assertEqual(products.count('|o1:1|'), 4)
def test_reaction_copies_stereogroup(self):
"""
If multiple copies of an atom in StereoGroup show up in the product, they
should all be part of the same product StereoGroup.
"""
# Stereogroup atoms are in the reaction with multiple copies in the product
products = _reactAndSummarize('[O:1].[C:2]=O>>[O:1][C:2][O:1]',
'Cl[C@@H](Br)C[C@H](Br)CCO |&1:1,4|',
'CC(=O)C')
# stereogroup manually checked, product SMILES assumed correct.
self.assertEqual(
products,
'CC(C)(OCC[C@@H](Br)C[C@@H](Cl)Br)OCC[C@@H](Br)C[C@@H](Cl)Br |&1:6,9,15,18|'
)
# Stereogroup atoms are not in the reaction, but have multiple copies in the
# product.
products = _reactAndSummarize('[O:1].[C:2]=O>>[O:1][C:2][O:1]',
'Cl[C@@H](Br)C[C@H](Br)CCO |&1:1,4|',
'CC(=O)C')
# stereogroup manually checked, product SMILES assumed correct.
self.assertEqual(
products,
'CC(C)(OCC[C@@H](Br)C[C@@H](Cl)Br)OCC[C@@H](Br)C[C@@H](Cl)Br |&1:6,9,15,18|'
)
if __name__ == '__main__':
unittest.main(verbosity=True)

91
Code/GraphMol/ChemReactions/catch_tests.cpp
View File

@@ -22,6 +22,7 @@
#include <GraphMol/ChemReactions/ReactionUtils.h>
using namespace RDKit;
using std::unique_ptr;
TEST_CASE("Github #1632", "[Reaction,PDB,bug]") {
SECTION("basics") {
@@ -30,7 +31,7 @@ TEST_CASE("Github #1632", "[Reaction,PDB,bug]") {
std::unique_ptr<RWMol> mol(SequenceToMol("K", sanitize, flavor));
REQUIRE(mol);
REQUIRE(mol->getAtomWithIdx(0)->getMonomerInfo());
auto res = static_cast<AtomPDBResidueInfo *>(
auto res = static_cast<AtomPDBResidueInfo*>(
mol->getAtomWithIdx(0)->getMonomerInfo());
CHECK(res->getResidueNumber() == 1);
std::unique_ptr<ChemicalReaction> rxn(RxnSmartsToChemicalReaction(
@@ -45,9 +46,95 @@ TEST_CASE("Github #1632", "[Reaction,PDB,bug]") {
auto p = prods[0][0];
CHECK(p->getNumAtoms() == mol->getNumAtoms() + 1);
REQUIRE(p->getAtomWithIdx(0)->getMonomerInfo());
auto pres = static_cast<AtomPDBResidueInfo *>(
auto pres = static_cast<AtomPDBResidueInfo*>(
p->getAtomWithIdx(0)->getMonomerInfo());
CHECK(pres->getResidueNumber() == 1);
REQUIRE(!p->getAtomWithIdx(4)->getMonomerInfo());
}
}
static void clearAtomMappingProps(ROMol& mol) {
for (auto&& a : mol.atoms()) {
a->clear();
}
}
TEST_CASE("Github #2366 Enhanced Stereo", "[Reaction,StereoGroup,bug]") {
SECTION("Reaction Preserves Stereo") {
ROMOL_SPTR mol("F[C@H](Cl)Br |o1:1|"_smiles);
REQUIRE(mol);
unique_ptr<ChemicalReaction> rxn(
RxnSmartsToChemicalReaction("[C@:1]>>[C@:1]"));
REQUIRE(rxn);
MOL_SPTR_VECT reactants = {mol};
rxn->initReactantMatchers();
auto prods = rxn->runReactants(reactants);
REQUIRE(prods.size() == 1);
REQUIRE(prods[0].size() == 1);
auto p = prods[0][0];
clearAtomMappingProps(*p);
CHECK(MolToCXSmiles(*p) == "F[C@H](Cl)Br |o1:1|");
}
SECTION("Reaction destroys one center in StereoGroup") {
ROMOL_SPTR mol("F[C@H](Cl)[C@@H](Cl)Br |&1:1,3|"_smiles);
REQUIRE(mol);
unique_ptr<ChemicalReaction> rxn(
RxnSmartsToChemicalReaction("[C@:1]F>>[C:1]F"));
REQUIRE(rxn);
MOL_SPTR_VECT reactants = {mol};
rxn->initReactantMatchers();
auto prods = rxn->runReactants(reactants);
REQUIRE(prods.size() == 1);
REQUIRE(prods[0].size() == 1);
auto p = prods[0][0];
clearAtomMappingProps(*p);
CHECK(MolToCXSmiles(*p) == "FC(Cl)[C@@H](Cl)Br |&1:3|");
}
SECTION("Reaction splits StereoGroup") {
ROMOL_SPTR mol("F[C@H](Cl)[C@@H](Cl)Br |&1:1,3|"_smiles);
REQUIRE(mol);
unique_ptr<ChemicalReaction> rxn(RxnSmartsToChemicalReaction(
"[F:1][C@:2][C@:3][Cl:4]>>[F:1][C@:2]O.O[C@:3][Cl:4]"));
REQUIRE(rxn);
MOL_SPTR_VECT reactants = {mol};
rxn->initReactantMatchers();
auto prods = rxn->runReactants(reactants);
REQUIRE(prods.size() == 1);
REQUIRE(prods[0].size() == 2);
auto p0 = prods[0][0];
auto p1 = prods[0][1];
clearAtomMappingProps(*p0);
clearAtomMappingProps(*p1);
CHECK(MolToCXSmiles(*p0) == "O[C@@H](F)Cl |&1:1|");
CHECK(MolToCXSmiles(*p1) == "O[C@@H](Cl)Br |&1:1|");
}
SECTION("Reaction combines StereoGroups") {
ROMOL_SPTR mol1("F[C@H](Cl)O |&1:1|"_smiles);
REQUIRE(mol1);
ROMOL_SPTR mol2("Cl[C@H](Br)O |&1:1|"_smiles);
REQUIRE(mol2);
unique_ptr<ChemicalReaction> rxn(RxnSmartsToChemicalReaction(
"[F:1][C@:2]O.O[C@:3][Cl:4]>>[F:1][C@:2][C@:3][Cl:4]"));
REQUIRE(rxn);
MOL_SPTR_VECT reactants = {mol1, mol2};
rxn->initReactantMatchers();
auto prods = rxn->runReactants(reactants);
REQUIRE(prods.size() == 1);
REQUIRE(prods[0].size() == 1);
auto p0 = prods[0][0];
clearAtomMappingProps(*p0);
CHECK(MolToCXSmiles(*p0) == "F[C@@H](Cl)[C@H](Cl)Br |&1:1,&2:3|");
}
}

37
Docs/Book/RDKit_Book.rst
View File

@@ -419,7 +419,8 @@ defition is handled. A consistent example, esterification of secondary
alcohols, is used throughout [#chiralRxn]_.
If no chiral information is present in the reaction definition, the
stereochemistry of the reactants is preserved:
stereochemistry of the reactants is preserved, as is membership in
enhanced stereo groups:
.. doctest::
@@ -1223,21 +1224,37 @@ and the set of atoms that make it up.
Use cases
=========
The initial target is to not lose data on an ``V3k mol -> RDKit -> V3k mol`` round trip. Manipulation,
depiction, and searching is a secondary goal.
The initial target is to not lose data on an ``V3k mol -> RDKit -> V3k mol`` round trip. Manipulation, depiction, and searching are future goals.
It is currently possible to enumerate the elements of a ``StereoGroup`` using the function py:func:`rdkit.Chem.EnumerateStereoisomers.EumerateStereoisomers`.
It is possible to enumerate the elements of a ``StereoGroup`` using the function :py:func:`rdkit.Chem.EnumerateStereoisomers.EumerateStereoisomers`, which also
preserves membership in the original ``StereoGroup``.
.. doctest ::
>>> m = Chem.MolFromSmiles('C[C@H](F)C[C@H](O)Cl |&1:1|')
>>> m.GetStereoGroups()[0].GetGroupType()
>>> m = Chem.MolFromSmiles('C[C@H](F)C[C@H](O)Cl |&1:1|')
>>> m.GetStereoGroups()[0].GetGroupType()
rdkit.Chem.rdchem.StereoGroupType.STEREO_AND
>>> [x.GetIdx() for x in m.GetStereoGroups()[0].GetAtoms()]
>>> [x.GetIdx() for x in m.GetStereoGroups()[0].GetAtoms()]
[1]
>>> from rdkit.Chem.EnumerateStereoisomers import EnumerateStereoisomers
>>> [Chem.MolToSmiles(x) for x in EnumerateStereoisomers(m)]
['C[C@@H](F)C[C@H](O)Cl', 'C[C@H](F)C[C@H](O)Cl']
>>> from rdkit.Chem.EnumerateStereoisomers import EnumerateStereoisomers
>>> [Chem.MolToCXSmiles(x) for x in EnumerateStereoisomers(m)]
['C[C@@H](F)C[C@H](O)Cl |&1:1|', 'C[C@H](F)C[C@H](O)Cl |&1:1|']
Reactions also preserve ``StereoGroup``s. Product atoms are included in the ``StereoGroup`` as long as the reaction doesn't create or destroy chirality at the atom.
.. doctest ::
>>> def clearAllAtomProps(mol):
... """So that atom mapping isn't shown"""
... for atom in mol.GetAtoms():
... for key in atom.GetPropsAsDict():
... atom.ClearProp(key)
...
>>> rxn = AllChem.ReactionFromSmarts('[C:1]F >> [C:1]Br')
>>> ps=rxn.RunReactants([m])
>>> clearAllAtomProps(ps[0][0])
>>> Chem.MolToCXSmiles(ps[0][0])
'C[C@H](Br)C[C@H](O)Cl |&1:1|'
.. rubric:: Footnotes

15
Docs/Code/EnhancedStereo.md
View File

@@ -32,17 +32,24 @@ depiction, and searching is a secondary goal.
Stored as a vector of `StereoGroup` objects.
A `StereoGroup` contains an enum with the type as well as pointers to the atoms involved. We will need to adjust this when atoms are removed or replaced. `StereoGroup`s are not exposed to Python, as the implementation is still tentative.
A `StereoGroup` contains an enum with the type as well as pointers to the atoms involved. We will need to adjust this when atoms are removed or replaced.
## Enumeration
The existing stereoisomer enumeration code needs to be updated to handle enhanced stereo groups correctly. This is the key piece for canonicalization and substructure searching.
The Python-only function `rdkit.Chem.EnumerateStereoisomers.EnumerateStereoisomers` can be used to enumerate
all stereoisomers represented by the StereoGroups. It is possible to enumerate _only_ the Stereo Groups,
ignoring other unspecified centers.
We probably need to add an option to allow enumeration only of stereo groups (to ignore unspecified centers).
## Reactions
The reaction runner is aware of stereo groups associated with a Mol. Atoms in a Stereo Group are copied to
all products in which they appear, unless the reaction created or destroyed stereochemistry at that atom.
If an atom from a reactant StereoGroup appears multiple times in the product, all copies of that atom are
put in the same product StereoGroup.
## Searching
This will be handled by searching in MolBundle objects produced by the enumeration code.
This will be handled by searching in MolBundle objects produced by the enumeration code. Substructure searching and canonicalization do not yet support stereo groups.
## Depiction

83
enhanced_stereo_in_reactions_demo.py Normal file
View File

@@ -0,0 +1,83 @@
from rdkit import Chem
from rdkit.Chem import AllChem
def get_product_cxsmiles(product):
# Clear properties. Mapping properties show up in CXSMILES
for a in product.GetAtoms():
for k in a.GetPropsAsDict():
a.ClearProp(k)
return Chem.MolToCXSmiles(product)
def print_rxn(rxn_smarts, smiles, comment):
print(f"\n{comment}:\n {rxn_smarts}")
print(' ', ' + '.join(smiles))
rxn = AllChem.ReactionFromSmarts(rxn_smarts)
mols = [Chem.MolFromSmiles(s) for s in smiles]
for prods in rxn.RunReactants(mols):
print(' >>')
print(' ', ' + '.join(map(get_product_cxsmiles, prods)))
# StereoGroup atoms are in the reaction, but the reaction doesn't affect
# the chirality at the stereo centers
# -> preserve stereo group
print_rxn('[C@:1]>>[C@:1]', ['F[C@H](Cl)Br |o1:1|'], '0a. Reaction preserves stereo')
print_rxn('[C@:1]>>[C@:1]', ['F[C@@H](Cl)Br |&1:1|'], '0b. Reaction preserves stereo')
print_rxn('[C@:1]>>[C@:1]', ['FC(Cl)Br'], '0c. Reaction preserves stereo')
# StereoGroup atoms are in the reaction, but the reaction doesn't specify the
# chirality at the stereo centers
# -> preserve stereo group
print_rxn('[C:1]>>[C:1]', ['F[C@H](Cl)Br |a:1|'], '1a. Reaction ignores stereo')
print_rxn('[C:1]>>[C:1]', ['F[C@@H](Cl)Br |&1:1|'], '1b. Reaction ignores stereo')
print_rxn('[C:1]>>[C:1]', ['FC(Cl)Br'], '1c. Reaction ignores stereo')
# StereoGroup atoms are in the reaction, and the reaction inverts the specified
# chirality at the stereo centers
# -> preserve stereo group
print_rxn('[C@:1]>>[C@@:1]', ['F[C@H](Cl)Br |o1:1|'], '2a. Reaction inverts stereo')
print_rxn('[C@:1]>>[C@@:1]', ['F[C@@H](Cl)Br |&1:1|'], '2b. Reaction inverts stereo')
print_rxn('[C@:1]>>[C@@:1]', ['FC(Cl)Br'], '2c. Reaction inverts stereo')
# StereoGroup atoms are in the reaction, and the reaction destroys the specified
# chirality at the stereo centers
# -> invalidate stereo group
print_rxn('[C@:1]>>[C:1]', ['F[C@H](Cl)Br |o1:1|'], '3a. Reaction destroys stereo')
print_rxn('[C@:1]>>[C:1]', ['F[C@@H](Cl)Br |&1:1|'], '3b. Reaction destroys stereo')
print_rxn('[C@:1]>>[C:1]', ['FC(Cl)Br'], '3c. Reaction destroys stereo')
print_rxn('[C@:1]F>>[C:1]F', ['F[C@H](Cl)[C@@H](Cl)Br |o1:1,&2:3|'], '3d. Reaction destroys stereo (but preserves unaffected group)' )
#### -> Should the group be invalidated or trimmed?
print_rxn('[C@:1]F>>[C:1]F', ['F[C@H](Cl)[C@@H](Cl)Br |&1:1,3|'], '3e. Reaction destroys stereo' )
# StereoGroup atoms are in the reaction, and the reaction creates the specified
# chirality at the stereo centers
# -> invalidate stereo group
print_rxn('[C:1]>>[C@@:1]', ['F[C@H](Cl)Br |o1:1|'], '4a. Reaction creates stereo')
print_rxn('[C:1]>>[C@@:1]', ['F[C@@H](Cl)Br |&1:1|'], '4b. Reaction creates stereo')
print_rxn('[C:1]>>[C@@:1]', ['FC(Cl)Br'], '4c. Reaction creates stereo')
print_rxn('[C:1]F>>[C@@:1]F', ['F[C@H](Cl)[C@@H](Cl)Br |o1:1,&2:3|'], '4d. Reaction creates stereo (preserve unaffected group)' )
#### -> Should the group be invalidated or trimmed?
print_rxn('[C:1]F>>[C@@:1]F', ['F[C@H](Cl)[C@@H](Cl)Br |o1:1,3|'], '4e. Reaction creates stereo' )
# StereoGroup atoms are not in the reaction
# -> preserve stereo group
print_rxn('[C@:1]F>>[C@:1]F', ['F[C@H](Cl)[C@@H](Cl)Br |o1:3|'], '5a. Reaction preserves unrelated stereo' )
print_rxn('[C:1]F>>[C:1]F', ['F[C@H](Cl)[C@@H](Cl)Br |o1:3|'], '5b. Reaction ignores unrelated stereo' )
print_rxn('[C@:1]F>>[C@@:1]F', ['F[C@H](Cl)[C@@H](Cl)Br |o1:3|'], '5c. Reaction inverts unrelated stereo' )
print_rxn('[C@:1]F>>[C:1]F', ['F[C@H](Cl)[C@@H](Cl)Br |o1:3|'], '5d. Reaction destroys unrelated stereo' )
print_rxn('[C:1]F>>[C@@:1]F', ['F[C@H](Cl)[C@@H](Cl)Br |o1:3|'], '5e. Reaction creates unrelated stereo' )
# StereoGroup atoms are split into two products by the reaction
#### -> Should the group be invalidated or trimmed?
print_rxn('[C:1]OO[C:2]>>[C:2]O.O[C:1]', ['F[C@H](Cl)OO[C@@H](Cl)Br |o1:1,5|'], '6e. Reaction splits StereoGroup atoms into two Mols' )
# Stereogroup atoms are in the reaction with multiple copies in the product
# -> All copies should be in the same product stereo group
print_rxn('[O:1].[C:2]=O>>[O:1][C:2][O:1]', ['Cl[C@@H](Br)C[C@H](Br)CCO |&1:1,4|', 'CC(=O)C'], '7. Add two copies')
# Stereogroup atoms are not in the reaction, but have multiple copies in the
# product.
# -> All copies should be in the same product stereo group
print_rxn('[O:1].[C:2]=O>>[O:1][C:2][O:1]', ['Cl[C@@H](Br)C[C@H](Br)CCO |&1:1,4|', 'CC(=O)C'], '8. Add two copies')